1-Aryl 2-aminomethyl cyclopropane carboxylates (Z) as drugs in the treatment of pain

ABSTRACT

The present invention concerns new derivatives of 1-aryl 2-aminomethyl cyclopropane carboxylates (Z), their preparation and their use as useful drugs for the treatment of various pains. 
     The new derivatives of the present invention have the general formula I ##STR1## in which: R represents a hydrogen or halogen atom, a C 1  to C 4  lower alkyl group, a C 1  to C 4  lower alkoxy group, or a nitro, amino, sulfamoyl or hydroxy group; 
     n represents the values 1, 2 or 3; 
     (R) n  may together with the benzene ring also form the naphthyl group; 
     R 1  represents a linear or branched C 1  to C 5  alkyl or alkenyl group or an aryl or benzyl group; 
     R 2  and R 3  represent a hydrogen atom, a linear or branched C 1  to C 5  alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl or dialkylaminoalkyl group or an aryl, arylalkyl or cycloalkyl group; 
     R 2  and R 3  possibly also forming a heterocycle of 5 or 6 members with the adjacent nitrogen atom, 
     provided however that when R 1  represents the ethyl radical and R represents a hydrogen atom, R 2  and R 3  cannot simultaneously represent a methyl radical.

The present invention, made at the Pierre FABRE Research Center, concerns new derivatives of 1-aryl 2-aminomethyl cyclopropane carboxylic esters (Z), their method of preparation and their use in therapy and in particular in the treatment of various pains.

The closest known prior art can be illustrated, for instance, by French Pat. No. 75 07120 which covers a method of preparing 1-aryl 2-hydroxymethyl cyclopropane carboxylic acids.

These acid-alcohol derivatives have furthermore been the subject matter of an article by G. MOUZIN, H. COUSSE and B. BONNAUD in "Synthesis 1978, 304," reprinted in "Synthetic Methods of Organic Chemistry" (Editor W. THEILHEIMER) 34, 1980, 317. The pharmacological study of the derivatives of 1-phenyl 2-hydroxymethyl cyclopropane carboxylic acid described by S. CASADIO, B. BONNAUD, G. MOUZIN and H. COUSSE in Boll. Chim. Farm. 117, 1978, 331, has shown the slight pharmacological activity of these derivatives.

The present invention relates to new compounds, which differ from those of the prior art indicated above; they are amino cyclopropane ester derivatives of the formula: ##STR2##

Now it has been shown that the modulations effected at the level of the functional groups borne by the cyclopropane group confer very interesting pharmacological properties to these new amino cyclopropane esters and more particularly an analgesic action which makes it possible to use these compounds for the treatment of various pains.

The present invention concerns new 1-aryl 2-aminomethyl cyclopropane carboxylate derivatives (Z) of general formula I: ##STR3## in which: R represents a hydrogen or halogen atom, a lower alkyl group of C₁ to C₄, lower alkoxy of C₁ to C₄, hydroxy, nitro, amino or sulfamoyl;

n represents 1, 2 or 3;

(R)_(n) may also, together with the benzene cycle, form the naphthyl group;

R₁ represents a C₁ to C₅ linear or branched alkenyl or alkyl group or an aryl or benzyl group;

R₂ and R₃ represent a hydrogen atom, a C₁ to C₅ linear or branched alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl or dialkylaminoalkyl group, or an aryl, arylalkyl or cycloalkyl group;

R₂ and R₃ possibly also forming with the neighboring nitrogen atom a heterocycle having 5 or 6 members,

provided however that when R₁ represents the ethyl radical and R represents a hydrogen atom, R₂ and R₃ cannot simultaneously represent a methyl radical. All numbers of carbon atoms given are inclusive of the largest number stated.

The heterocycle formed by the radicals R₂ and R₃ with the neighboring nitrogen atom designates more particularly a heterocycle of a non-aromatic character with five or six members which may possibly contain one or more other heteroatoms selected primarily from among nitrogen and oxygen and being possibly furthermore substituted, for instance in para position of the said adjacent nitrogen atom or on the second heteroatom, by an aryl radical, particularly a phenyl radical which in its turn is substituted by one or more other halogen atoms, such as chlorine.

The present invention also relates to salts of compounds of general formula I with therapeutically acceptable inorganic or organic acids. By way of illustration and not of limitation of these salts, mention may be made of the hydrohalides such as hydrochloride, fumarate, maleate, oxalate, citrate and glutamate.

The present invention also concerns a method of preparing compounds of general formula (I) consisting in treating the lactone of general formula (II) by an alcohol or a phenol in the presence of a thionyl halide. The lactone of the general formula (II) can for instance be obtained by the method of preparation described in the applicant's French Pat. No. 75 07120. The halogenated intermediary of general formula (III) is then condensed on an amine. The method of preparation is illustrated by the following reaction scheme. ##STR4## in which X represents a halogen

R, R₁, R₂, R₃ and n have the meaning given previously in connection with general formula (I).

The following examples illustrate the invention without, of course, limiting its scope. In the formulas of the compounds of the following examples the symbol Et designates the ethyl radical.

EXAMPLE 1 Preparation of the hydrochloride of 1-phenyl-1-ethoxycarbonyl-2-pyrrolidinomethyl cyclopropane (Z) (a) Preparation of the 1-phenyl 1-ethoxycarbonyl 2-chloromethyl cyclopropane (Z)

126 cc (1.8 mole) of thionyl chloride are introduced with agitation over the course of 21/2 hours into 500 cc of ethanol at -10° C. whereupon 100 g (0.57 mole) of 1-phenyl 2-oxo 3-oxa bicyclo(3.1.0)hexane are added. The mixture is allowed to return to room temperature while agitated for 12 hours.

The reaction solvent is evaporated and rectified under reduced pressure.

A product of the formula ##STR5## is recovered in a yield of 95%.

Empirical formula: C₁₃ H₁₅ ClO₂.

Molecular weight: 238.71.

Boiling point: 95°-98° C./0.04 mm Hg.

Melting point: 45°-45° C.

(b) 1-phenyl 1-ethoxycarbonyl-2-pyrrolidinomethyl cyclopropane hydrochloride (Z)

To a solution of (0.03 mole) of 1-phenyl 1-ethoxy carbonyl 2-chloromethyl cyclopropane (Z) in 60 cc of toluene there are added 6.4 g (0.09 mole) of pyrrolidine.

The reaction solution is maintained under reflux for five hours. The solvent is evaporated to dryness.

The residual mass is treated with a bicarbonate solution; it is extracted with ethyl ether and then washed with water and dried over sodium sulfate.

The free base is treated with an ethanol solution saturated with hydrochloric acid; upon the addition of ether the salt precipitates and the product of the formula ##STR6## is recovered in a yield of 85%.

Empirical formula: C₁₇ H₂₄ ClNO₂.

Molecular weight: 309.8.

Crystals: white.

Melting point: 140° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.49.

Solubility: 50% soluble in water.

EXAMPLE 2 Hydrochloride of 1-phenyl-1-ethoxycarbonyl-2-(2-phenyl ethyl)amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using 2-phenyl ethylamine, there is obtained the product of the formula: ##STR7##

Empirical formula: C₂₁ H₂₆ ClNO₂.

Molecular weight: 359.9.

Crystals: white.

Melting point: 156° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform-methanol.

development: UV and iodine.

Rf: 0.62.

Solubility: 50% soluble in water.

EXAMPLE 3 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-methyl amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using methylamine, the product of the formula: ##STR8## is obtained.

Empirical formula: C₁₄ H₂₀ ClNO₂.

Molecular weight: 269.8.

Crystals: white.

Melting point: 132° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.54.

Solubility: 50% soluble in water.

EXAMPLE 4 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-diethyl amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using diethylamine a product of the formula ##STR9## is obtained.

Empirical formula: C₁₇ H₂₆ ClNO₂.

Molecular weight: 311.86.

Crystals: white.

Melting point: 132° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.44.

Solubility: 50% soluble in water.

EXAMPLE 5 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-(benzyl methyl amino methyl)cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl benzylamine, the product of the formula ##STR10## is obtained.

Empirical formula: C₂₁ H₂₆ ClNO₂.

Molecular weight: 359.9.

Crystals: white.

Melting point: 130° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.6.

Solubility: 10% soluble in water.

EXAMPLE 6 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-tertbutylamino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using terbutylamine, there is obtained the product of the formula: ##STR11##

Empirical formula: C₁₇ H₂₆ ClNO₂.

Molecular weight: 311.85.

Crystals: white.

Melting point: 155° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.59.

Solubility: 17% soluble in water.

EXAMPLE 7 Maleate of 1-phenyl 1-ethoxycarbonyl 2-di(2'-hydroxyethyl)amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using diethanolamine and maleic acid as salifying agent, there is obtained a product of the formula: ##STR12##

Empirical formula: C₂₁ H₂₉ NO₈.

Molecular weight: 423.4.

Crystals: white.

Melting point: 102° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.47.

Solubility: 50% soluble in water.

EXAMPLE 8 Dihydrochloride of 1-phenyl 1-ethoxycarbonyl 2-(4'-phenyl-piperazino methyl)cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-phenyl piperazine, there is obtained a product of the formula: ##STR13##

Empirical formula: C₂₃ H₃₀ Cl₂ N₂ O₂.

Molecular weight: 437.4.

Crystals: white.

Melting point: 202° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.72.

Solubility: 0.5% soluble in water.

EXAMPLE 9 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-morpholino methyl cyclopropane (Z)

In a manner similar to that described in Example 1b but using morpholine, there is obtained a product of the formula: ##STR14##

Empirical formula: C₁₇ H₂₄ ClNO₃.

Molecular weight: 325.8.

Crystals: white.

Melting point: 195° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.52.

Solubility: 50% soluble in water.

EXAMPLE 10 Fumarate of 1-phenyl 1-ethoxycarbonyl 2-N-(2'-hydroxyethyl)N-methyl amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b but using N-methyl ethanolamine and fumaric acid as salifying agent, there is obtained a product of the formula: ##STR15##

Empirical formula: C₂₀ H₂₇ NO₇.

Molecular weight: 393.42.

Crystals: white.

Melting point: 139° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.4.

Solubility: 8% soluble in water.

EXAMPLE 11 Hydrochloride of 1-phenyl-1-ethoxycarbonyl 2-dibenzyl amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using dibenzylamine, there is obtained a product of the formula: ##STR16##

Empirical formula: C₂₇ H₃₀ ClNO₂.

Molecular weight: 436.

Crystals: white.

Melting point: 185° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.77.

Solubility: insoluble in water, 2% soluble in DMA.

EXAMPLE 12 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-(1'-1'-dimethyl-2'-propynyl amino methyl)cyclopropane (Z)

In a manner similar to that described in Example 1b, but using 2-amino-2-methyl-3-butyne, there is obtained a product of the formula: ##STR17##

Empirical formula: C₁₈ H₂₄ ClNO₂.

Molecular weight: 321.8.

Crystals: white.

Melting point: 194° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.65.

Solubility: 3% soluble in water

EXAMPLE 13 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-(2'-ethoxy ethylaminomethyl)cyclopropane (Z)

In a manner similar to that described in Example 1b, but using 2-ethoxy ethylamine, there is obtained a product of the formula: ##STR18##

Empirical formula: C₁₇ H₂₆ CLNO₃.

Molecular weight: 327.8.

Crystals: white.

Melting point: 100° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.59.

Solubility: 50% soluble in water.

EXAMPLE 14 Hydrochloride of 1-phenyl-1-ethoxycarbonyl 2-benzyl amino methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using benzylamine, there is obtained a product of the formula: ##STR19##

Empirical formula: C₂₀ H₂₄ ClNO₂.

Molecular weight: 345.9.

Crystals: white.

Melting point: 180° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.65.

Solubility: 1% soluble in water

EXAMPLE 15 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-isopropyl aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using isopropylamine, there is obtained a product of the formula: ##STR20##

Empirical formula: C₁₆ H₂₄ ClNO₂.

Molecular weight: 297.8.

Crystals: white.

Melting point: 131° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.52.

Solubility: 50% soluble in water.

EXAMPLE 16 Maleate of 1-phenyl 1-ethoxycarbonyl 2-diisopropyl aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using diisopropylamine and maleic acid as salifying agent, there is obtained a product of the formula: ##STR21##

Empirical formula: C₂₃ H₃₃ NO₆.

Molecular weight: 419.5.

Crystals: white.

Melting point: 108° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.5.

Solubility: 10% soluble in water.

EXAMPLE 17 Fumarate of 1-phenyl 1-ethoxycarbonyl 2-(N-methyl-N-ethyl-amino)methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl-N-ethylamine, and fumaric acid as salifying agent, there is obtained a product of the formula: ##STR22##

Empirical formula: C₂₀ H₂₇ NO₆.

Molecular weight: 377.4.

Crystals: white.

Melting point: 98° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.45.

Solubility: 50% soluble in water

EXAMPLE 18 Fumarate of 1-phenyl 1-ethoxycarbonyl 2-(N-methyl-N-pentylamino)methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl pentylamine and fumaric acid as salifying agent, there is obtained a product of the formula: ##STR23##

Empirical formula: C₂₃ H₃₃ NO₆.

Molecular weight: 419.5.

Crystals: white.

Melting point: 100° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.61.

Solubility: 3% soluble in water.

EXAMPLE 19 Fumarate of 1-phenyl 1-ethoxycarbonyl 2-N-methyl-N-cyclohexyl-aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl cyclohexylamine and fumaric acid as salifying agent, there is obtained a product of the formula: ##STR24##

Empirical formula: C₂₄ H₃₃ NO₆.

Molecular weight: 431.5.

Crystals: white.

Melting point: 179° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.56.

Solubility: insoluble in water, 5% soluble in DMA

EXAMPLE 20 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-(4'-phenyl piperidino)methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using 4-phenyl piperidine, there is obtained a product of the formula: ##STR25##

Empirical formula: C₂₄ H₃₀ ClNO₂.

Molecular weight: 399.9.

Crystals: white.

Melting point: 165° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.71.

Solubility: insoluble in water, 50% soluble in DMA

EXAMPLE 21 Dihydrochloride of 1-phenyl 1-ethoxycarbonyl-2-(N-methyl N-(2'-dimethylamino)ethyl)aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N,N,N'-trimethyl ethylene diamine, there is obtained a product of the formula: ##STR26##

Empirical formula: C₁₈ H₃₀ Cl₂ N₂ O₂.

Molecular weight: 377.3.

Crystals: white.

Melting point: 210° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/ammonia 80/18/2.

development: UV and iodine.

Rf: 0.55.

Solubility: 50% soluble in water

EXAMPLE 22 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-cyclohexylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using cyclohexylamine, there is obtained a product of the formula: ##STR27##

Empirical formula: C₁₉ H₂₈ ClNO₂.

Molecular weight: 377.9.

Crystals: white.

Melting point: 152° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol 85/15.

development: UV and iodine.

Rf: 0.45.

EXAMPLE 23 Hydrochloride of 1-phenyl 1-ethoxycarbonyl-2-piperidino methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using piperidine, there is obtained a product of the formula: ##STR28##

Empirical formula: C₁₈ H₂₆ ClNO₂.

Molecular weight: 323.8.

Crystals: white.

Melting point: 175° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol 85/15.

development: UV and iodine.

Rf: 0.59.

EXAMPLE 24 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-N-methyl N-phenyl aminomethyl cyclopropane (Z)

In a manner similar to that described in FIG. 1b, but using N-methyl aniline, there is obtained a product of the formula: ##STR29##

Empirical formula: C₂₀ H₂₄ ClNO₂.

Molecular weight: 345.8.

Crystals: white.

Melting point: 120° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: ether of ethyl petroleum acetate 90/10.

development: UV and iodine.

Rf: 0.3.

EXAMPLE 25 Dihydrochloride of 1-phenyl 1-ethoxycarbonyl-2-[4'-(metachlorophenyl)piperazino]methyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using 4-metachlorophenyl piperazine, there is obtained a product of the formula: ##STR30##

Empirical formula: C₂₃ H₂₉ Cl₃ N₂ O₂.

Molecular weight: 471.8.

Crystals: white.

Melting point: 185° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.71.

EXAMPLE 26 Oxalate of 1-phenyl 1-ethoxycarbonyl 2-N-methyl-N-allyl aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl allylamine and oxalic acid as salifying agent, there is obtained a product of the formula: ##STR31##

Empirical formula: C₁₉ H₂₅ NO₆.

Molecular weight: 327.4.

Crystals: white.

Melting point: 128° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.5.

EXAMPLE 27 1-phenyl 1-ethoxycarbonyl 2-N-ethyl-N-(2-ethoxyethyl)aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-ethyl-2-ethoxy ethylamine, there is obtained a product of the formula ##STR32##

Empirical formula: C₁₉ H₂₉ NO₃.

Molecular weight: 319.2.

Boiling point: 120° C./10⁻² mm Hg.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: ethyl acetate/petroleum ether 50/50.

development: UV and iodine.

Rf: 0.3.

EXAMPLE 28 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-[(2-methyl N-p-hydroxyphenyl ethyl)-aminomethyl]cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl tyramine, there is obtained a product of the formula: ##STR33##

Empirical formula: C₂₂ H₂₈ ClNO₃.

Molecular weight: 389.9.

Crystals: white.

Melting point: 157° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/ammonia.

development: UV and iodine.

Rf: 0.57.

EXAMPLE 29 Meleate of 1-phenyl 1-ethoxycarbonyl 2-(N-methyl-N-ethoxy carbonyl)aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using methyl sarcosinate, there is obtained a product of the formula: ##STR34##

Empirical formula: C₂₂ H₂₉ NO₈.

Molecular weight: 435.46.

Crystals: white.

Melting point: 84° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: petroleum ethyl ether acetate.

development: UV and iodine.

Rf: 0.49.

EXAMPLE 30 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2[N-methyl-2-N-phenyl ethyl)-aminomethyl]cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl phenyl ethylamine, there is obtained a product of the formula ##STR35##

Empirical formula: C₂₂ H₂₈ ClNO₂.

Molecular weight: 373.9.

Crystals: white.

Melting point: 112° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.66.

EXAMPLE 31 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-(1'-benzyl ethylamino methyl)-cyclopropane (Z)

In a manner similar to that described in Example 1b, but using DL amphetamine, there is obtained a product of the formula: ##STR36##

Empirical formula: C₂₂ H₂₈ ClNO₂.

Molecular weight: 373.9.

Crystals: white.

Melting point: 135° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol 5/95.

development: UV and iodine.

Rf: 0.33.

EXAMPLE 32 Hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-(N-methyl-N-butyl aminomethyl) cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl butylamine, there is obtained a product of the formula: ##STR37##

Empirical formula: C₁₈ H₁₇ ClNO₂.

Molecular weight: 325.9.

Crystals: white.

Melting point: 132° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.59.

EXAMPLE 33 1-phenyl 1-ethoxycarbonyl (N-methyl 2'-N-tetrahydrofurfuryl)-aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1b, but using N-methyl tetrahydrofurfurylamine, there is obtained a product of the formula: ##STR38##

Empirical formula: C₁₉ H₂₇ NO₃.

Molecular weight: 317.4.

Oil

Boiling point: 152° under a pressure of 10⁻¹ mmHg.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.41.

EXAMPLE 34 Hydrochloride of 1-phenyl 1-methoxycarbonyl 2-dimethyl-amino-methyl cyclopropane (Z)

In a manner similar to that described in Example 1a, but using methyl alcohol, and as in 1b using dimethylamine, there is obtained a product of the formula: ##STR39##

Empirical formula: C₁₄ H₂₀ ClNO₂.

Molecular weight: 269.7.

Crystals: white.

Melting point: 150° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

revelation: UV and iodine.

Solubility: 50% soluble in water.

EXAMPLE 35 Fumarate of 1-phenyl 1-propyloxycarbonyl 2-dimethyl aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1a, but using propyl alcohol and in 1b using dimethylamine and fumaric acid as salifying agent, there is obtained a product of the formula: ##STR40##

Empirical formula: C₂₀ H₂₇ NO₆.

Molecular weight: 377.4.

Crystals: white.

Melting point: 114° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/ammonia 80/18/2.

development: UV and iodine.

Rf: 0.76.

Solubility: 15% soluble in water.

EXAMPLE 36 Hydrochloride of 1-phenyl 1-isopropyloxy-carbonyl 2-dimethylamino methyl cyclopropane (Z)

In a manner similar to that described in Example 1a, but using isopropyl alcohol, and in 1b but using dimethylamine, there is obtained a product of the formula: ##STR41##

Empirical formula: C₁₆ H₂₄ ClNO₂.

Molecular weight: 297.8.

Crystals: white.

Melting point: 158° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.41.

EXAMPLE 37 Hydrochloride of 1-phenyl 1-benzyloxy carbonyl-2-dimethyl aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1a, but using benzyl alcohol, and in 1b but using dimethylamine, there is obtained a product of the formula: ##STR42##

Empirical formula: C₂₀ H₂₄ ClNO₂.

Molecular weight: 345.9.

Melting point: 132° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.52.

EXAMPLE 38 Hydrochloride of 1-phenyl 1-phenoxycarbonyl-2-dimethyl amino methyl cyclopropane (Z)

In a manner similar to that described in Example 1a, but using phenol and in 1b but using dimethylamine, there is obtained a product of the formula: ##STR43##

Empirical formula: C₁₉ H₂₂ ClNO₂.

Molecular weight: 315.8.

Crystals: white.

Melting point: 234° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.42.

EXAMPLE 39 Fumarate of 1-phenyl 1-allyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Examples 1a and 1b, but using allyl alcohol and dimethylamine, there is obtained a product of the formula: ##STR44##

Empirical formula: C₂₀ H₂₅ NO₆.

Molecular weight: 375.4.

Crystals: white.

Melting point: 92° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.4.

EXAMPLE 40 Fumarate of 1-phenyl 1-(3'-methyl-2-butenyloxy carbonyl)-2-dimethylaminomethyl cyclopropane

In a manner similar to that described in Examples 1a and 1b, but using 3-methyl-2-butene-1-ol and dimethylamine, there is obtained a product of the formula: ##STR45##

Empirical formula: C₂₂ H₂₉ NO₆.

Molecular weight: 403.6.

Crystals: clear beige.

Melting point: 114° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.36.

EXAMPLE 41 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) hydrochloride

In a manner similar to that described in Examples 1a and 1b, but using the lactone of 1-p(chlorophenyl) 2-hydroxymethyl cyclopropane (Z) carboxylic acid and dimethylamine, there is obtained a product of the formula: ##STR46##

Empirical formula: C₁₅ H₂₁ Cl₂ NO₂.

Molecular weight: 318.25.

Crystals: clear beige.

Melting point: 132° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/ammonia 84/14/2.

development: UV and iodine.

Rf: 0.7.

EXAMPLE 42 Hydrochloride of 1-(α-naphthyl) 1-ethoxycarbonyl 2-dimethylamino methyl cyclopropane (Z)

In a manner similar to that described in Examples 1a and 1b, but using the lactone of α-naphthyl 2-hydroxymethyl cyclopropane carboxylic acid (Z) and dimethylamine, there is obtained a product of the formula: ##STR47##

Empirical formula: C₁₉ H₂₄ ClNO₂.

Molecular weight: 333.86.

Crystals: white.

Melting point: 173° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.34.

EXAMPLE 43 Hydrochloride of 1-(4'-sulfamoyl phenyl) 1-methoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(4'-sulfamoyl phenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane, methyl alcohol and dimethylamine, there is obtained a product of the formula: ##STR48##

Empirical formula: C₁₄ H₂₁ ClNO₄ S.

Molecular weight: 348.8.

Crystals: clear beige.

Melting point: 214° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/water 65/25/4.

development: UV and iodine.

Rf: 0.25.

EXAMPLE 44 Maleate of 1-(m-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using the lactone of 1-(m-chlorophenyl) 2-hydroxymethyl cyclopropane carboxylic acid (Z) and dimethylamine, there is obtained a product of the formula: ##STR49##

Empirical formula: C₁₉ H₂₄ ClNO₆.

Molecular weight: 397.8.

Crystals: white.

Melting point: 85° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.42.

EXAMPLE 45 Hydrochloride of 1-(3,4 dichlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(3',4'-dichlorophenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, there is obtained a product of the formula: ##STR50##

Empirical formula: C₁₅ H₂₀ Cl₃ NO₂.

Molecular weight: 352.7.

Crystals: white.

Melting point: 148° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.37.

EXAMPLE 46 Maleate of 1-(p-aminophenyl 1-methyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(p-aminophenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane, methanol and dimethylamine, there is obtained a product of the formula: ##STR51##

Empirical formula: C₁₈ H₂₄ N₂ O₆.

Molecular weight: 364.4.

Crystals: white.

Melting point: 110° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/ammonia 80/18/2.

development: UV and iodine.

Rf: 0.66.

EXAMPLE 47 Hydrochloride of 1-(p-nitrophenyl) 1-methoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(4'-nitrophenyl) 2-oxo 3-oxa bicyclo(3:1:0) hexans, methanol and dimethylamine, there is obtained a product of the formula: ##STR52##

Empirical formula: C₁₄ H₁₉ ClN₂ O₄.

Molecular weight: 314.8.

Crystals: white.

Melting point: 210° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol/water 80/18/2.

development: UV and iodine.

Rf: 0.64.

EXAMPLE 48 Hydrochloride of 1-(p-methoxy phenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(p-methoxy phenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, there is obtained a product of the formula: ##STR53##

Empirical formula: C₁₆ H₂₄ ClNO₃.

Molecular weight: 313.8.

Crystals: white.

Melting point: 170° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water 6/2/2.

development: UV and iodine.

Rf: 0.49.

EXAMPLE 49 Hydrochloride of 1-p-toluyl 1-(2'-propenyloxy carbonyl) 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-p-toluyl 2-oxo 3-oxa bicyclo(3:1:0)hexane, allyl alcohol and dimethylamine, there is obtained a product of the formula: ##STR54##

Empirical formula: C₁₇ H₂₄ ClNO₂.

Molecular weight: 309.8.

Crystals: white.

Melting point: 154° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol 85/15.

development: UV and iodine.

Rf: 0.41.

EXAMPLE 50 Hydrochloride of 1-(3',4'-dichlorophenyl) 1-(2'-propenyloxy carbonyl) 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(3',4'-dichlorophenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane, allyl alcohol and dimethylamine, there is obtained a product of the formula: ##STR55##

Empirical formula: C₁₆ H₂₀ Cl₃ NO₂.

Molecular weight: 364.7.

Crystals: white.

Melting point: 160° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: chloroform/methanol 15/85.

development: UV and iodine.

Rf: 0.45.

EXAMPLE 51 Hydrochloride of 1-parafluorophenyl 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-p-fluorophenyl 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, there is obtained a product of the formula: ##STR56##

Empirical formula: C₁₅ H₂₁ FClNO₂.

Molecular weight: 301.7.

Crystals: white.

Melting point: 165° C.

Plate chromatography:

support: silica gel 60 F 254 Merck.

solvent: butanol/acetic acid/water.

development: UV and iodine.

Rf: 0.36.

EXAMPLE 52 Hydrochloride of 1-(p-chlorophenyl) 1-ethoxycarbonyl 2-aminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(p-chlorophenyl) 2-oxa 3-oxa bicyclo(3:1:0)hexane and ammonia, there is obtained a product of the formula: ##STR57##

EXAMPLE 53 Hydrochloride of 1-(p-hydroxyphenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(p-hydroxyphenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, there is obtained a product of the formula: ##STR58##

EXAMPLE 54 Hydrochloride of 1-(3',4',5'-trimethoxyphenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-(3',4',5'-trimethoxyphenyl) 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, there is obtained a product of the formula: ##STR59##

EXAMPLE 55 Hydrochloride of 1-orthobromophenyl 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z)

In a manner similar to that described in Example 1, but using 1-orthobromophenyl 2-oxo 3-oxa bicyclo(3:1:0)hexane and dimethylamine, the product of formula ##STR60## is obtained.

PHARMACOLOGICAL PROPERTIES (1) Toxicity Study

The most interesting compounds of the present invention were subjected to toxicity studies.

The ED₅₀ was determined orally and intraperitoneally and calculated by the method of MILLER and TAINTER (Proc. Soc. Exper. Biol. Chem. 1944, 57, 261).

The results are set forth in Table I below

                  TABLE I                                                          ______________________________________                                                                             Hot Plate                                                           Writhing   50 mg/kg                                            ED.sub.50                                                                              intra-  Syndrome   SC                                                  per os  perito- PBQ-ED.sub.50 mg/kg                                                                       reaction time                              PRODUCTS mg/kg   neally  (P.O.)     (seconds)                                  ______________________________________                                         Example 30                                                                              1000    110     80         20                                         Example 36                                                                              400     130     17         40                                         Example 37                                                                              1000    130     92         30                                         Example 41                                                                              400     120     19         39                                         Example 44                                                                              760     170     30         28                                         Example 45                                                                              550     170     60         26                                         Example 46                                                                              420     100     34         25                                         Example 47                                                                              1000    250     21         20                                         Example 48                                                                              420     110     95         29                                         Dextro-                  30         30                                         propoxyphene                                                                   ______________________________________                                    

(2) Analgesic Activity (a) Writhing Syndrome (P.B.Q.)

After I.P. administration of p-benzoquinone to mice, the products were tested by the method of R. OKUN, S. C. LIDDON and L. LASAGNA, J. Pharmacol. Exptl. Therap., 1963, 139, 107. The results are expressed in ED₅₀ in Table 1.

(b) Hot Plate

The products were tested subcutaneously in mice (50 mg/kg) by the method of N. B. EDDY and D. LEIMBACH, J. Pharm. Exptl. Therap., 1953, 107, 385. The results are set forth in Table 1.

(3) Therapeutic Applications

On basis of their pharmacological properties and their low toxicity, these compounds can be used in therapy in the treatment of various pains, most especially the compounds of Examples 36, 41, 44, 46 and 47.

These compounds and their addition salts with therapeutically compatible acids can be used as drugs, for instance, in the form of adapted pharmaceutical preparations which facilitate bioavailability.

These preparations may be in solid form, for instance tablets, pills, capsules, etc., or in liquid form, for instance solutions, suspensions, or emulsions.

The pharmacological preparations in a form suitable for injection are subjected to conventional pharmaceutical operations such as sterilization and/or may contain adjuvants, for instance preservatives, stabilizers, wetting or emulsifying agents, buffer compounds, etc.

The doses in which the active compounds and their addition salts with therapeutically compatible acids can be administered may vary in wide proportions depending on the condition of the patient. A daily dose of from about 0.1 mg to 1 mg/kg of body weight is, however, preferred.

The pharmaceutical compositions of the invention can be used in human or veterinary medicine, for instance in the treatment of painful phenomena, particularly in cancerology, traumatology, rheumatology, neurology and surgery.

Other active principles can be associated with the compounds of general formula I of the invention in order to supplement or reinforce their therapeutic action within a given pharmaceutical composition.

EXAMPLES OF PHARMACEUTICAL PREPARATIONS

    ______________________________________                                         A/ Tablets of prolonged effect                                                 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethyl-                                                         50 mg                                                aminomethyl cyclopropane (Z) hydrochloride                                     Retard excipient Q.S.P.  1 tablet                                              B/ Suppository                                                                 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethyl-                                                         25 mg                                                aminomethyl cyclopropane (Z) hydrochloride                                     Paracetamol              300 mg                                                Excipient Q.S.P.         1 adult                                                                        suppository                                           ______________________________________                                    

Of course, the present invention is not limited to the particular examples which have been given solely by way of illustration, but it is entirely possible to think of a number of variants and modifications thereof without thereby going beyond the scope of the invention. 

We claim:
 1. A pharmaceutical composition, useful for alleviation of pain, characterized by the fact that as active principle it contains at least one compound selected from (A) a 1-aryl 2-aminomethyl cyclopropane carboxylate (Z) of formula I: ##STR61## in which: R represents halogen, C₁ to C₄ alkoxy, nitro, amino, sulfamoyl, or hydroxy;n represents the value 1, 2 or 3; R₁ represents linear or branched C₁ to C₅ alkyl of alkenyl; R₂ and R₃ independently represent hydrogen or a linear or branched C₁ to C₅ alkyl or alkenyl, and (B) a salt thereof with a therapeutically-acceptable inorganic or organic acid.
 2. A pharmaceutical composition, useful for the alleviation of pain, comprising an effective pain-alleviating amount of a 1-phenyl 1-lower-alkoxycarbonyl 2-primary aminomethyl, monoloweralkylaminomethyl, or diloweralkylaminomethyl cyclopropane (Z), wherein the 1-phenyl radical is substituted by halo, amino, or nitro, or a pharmaceutically-acceptable acid addition salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
 3. Composition of claim 2 wherein the compound is a 2-dimethylaminomethyl compound.
 4. A pharmaceutical composition of claim 2, comprising an effective pain-alleviating amount of 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) hydrochloride.
 5. A pharamaceutical composition of claim 2, comprising an effective pain-alleviating amount of the maleate of 1-(p-aminophenyl) 1-methyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z).
 6. A pharmaceutical composition of claim 1, comprising an effective pain-alleviating amount of a 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) pharmaceutically-acceptable acid addition salt or a pharmaceutically-acceptable acid addition salt of 1-(p-aminophenyl) 1-methyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z).
 7. A method of alleviating pain comprising administering to a subject, suffering from pain, an effective pain-alleviating amount of a pharmaceutical composition of claim
 2. 8. Method of claim 7 wherein the compound is a 2-dimethylaminomethyl compound.
 9. A method of alleviating pain comprising administering to a subject, suffering from pain, an effective pain-alleviating amount of a 1-phenyl 1-lower-alkoxycarbonyl 2-primary aminomethyl, monoloweralkylaminomethyl, or diloweralkylaminomethyl cyclopropane (Z), wherein the 1-phenyl radical is substituted by halo, amino, or nitro, or a pharmaceutically acceptable acid addition salt thereof.
 10. Method of claim 9 wherein the compound is a 2-dimethylaminomethyl compound.
 11. A pharmaceutical composition, useful for the alleviation of pain, comprising an effective pain-alleviating amount of a 1-phenyl-1-loweralkoxycarbonyl 2-aminomethyl cyclopropane (Z), wherein the 1-phenyl radical is substituted by hydroxy, methoxy, halo, amino, or nitro, and wherein aminomethyl is primary aminomethyl, monoloweralkylaminomethyl, or diloweralkylaminomethyl, or a pharmaceutically-acceptable acid addition salt thereof, in admixture with a pharmaceutically-acceptable diluent or carrier.
 12. Composition of claim 11 wherein the compound is a 2-dimethylaminomethyl compound.
 13. A method of alleviating pain comprising administering to a subject, suffering from pain, an effective pain-alleviating amount of a pharmaceutical composition of claim
 11. 14. Method of claim 13 wherein the compound is a 2-dimethylaminomethyl compound.
 15. A method of alleviating pain comprising administering to a subject, suffering from pain, an effective pain-alleviating amount of a 1-phenyl-1-lower-alkoxycarbonyl 2-aminomethyl cyclopropane (Z), wherein the 1-phenyl radical is substituted by hydroxy, methoxy, halo, amino, or nitro, and wherein aminomethyl is primary aminomethyl, monoloweralkylaminomethyl, or diloweralkylaminomethyl, or a pharmaceutically-acceptable acid addition salt thereof.
 16. Method of claim 15 wherein the compound is a 2-dimethylaminomethyl compound.
 17. A method of alleviating pain comprising the step of administering to a subject, suffering from pain, an effective pain-alleviating amount of a 1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) pharmaceutically-acceptable acid addition salt or a pharmaceutically-acceptable acid addition salt of 1-(p-aminophenyl) 1-methyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z).
 18. A pharmaceutical composition, useful for the alleviation of pain, comprising an effective pain-alleviating amount of a compound selected from (A) 1-aryl 2-aminomethyl cyclopropane carboxylates (Z) of formula I: ##STR62## in which: R represents hydrogen or halogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, nitro, amino, sulfamoyl or hydroxy; n represents the values 1, 2 or 3; R₁ represents linear or branched C₁ to C₅ alkyl or alkenyl; R₂ and R₃ independently represent hydrogen, or linear or branched C₁ to C₅ alkyl or alkenyl, provided, however, that when R₁ represents the ethyl radical and R represents a hydrogen atom, R₂ and R₃ cannot simultaneously each represent a methyl radical, and (B) a salt thereof with a therapeutically-acceptable inorganic or organic acid, in admixture with a pharmaceutically-acceptable diluent or carrier.
 19. A pharmaceutical composition of claim 18, wherein R is chloro.
 20. A pharmaceutical composition of claim 18, wherein R is para-chloro.
 21. A method of alleviating pain comprising administering to a subject, suffering from pain, an effective pain-alleviating amount of a compound selected from (A) 1-aryl 2-aminomethyl cyclopropane carboxylates (Z) of formula I: ##STR63## in which: R represents hydrogen or halogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, nitro, amino, sulfamoyl or hydroxy; n represents the values 1, 2 or 3; R₁ represents linear or branched C₁ to C₅ alkyl or alkenyl; R₂ and R₃ independently represent hydrogen, or linear or branched C₁ to C₅ alkyl or alkenyl, provided, however, that when R₁ represents the ethyl radical and R represents a hydrogen atom, R₂ and R₃ cannot simultaneously each represent a methyl radical, and (B) a salt thereof with a therapeutically-acceptable inorganic or organic acid, or a pharmaceutical composition containing the said compound together with a pharmaceutically-acceptable diluent or carrier.
 22. A method of treating of claim 21, wherein R is chloro.
 23. A method of treating of claim 21, wherein R is para-chloro.
 24. A pharmaceutical composition, useful for alleviation of pain, characterized by the fact that as active principle it contains at least one compound selected from the group consisting of:1-(4'-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z) hydrochloride, the hydrochloride of 1-(4'-sulfamoylphenyl) 1-methoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the maleate of 1-(m-chlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(3,4-dichlorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the maleate of 1-(p-aminophenyl) 1-methyloxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(p-nitrophenyl) 1-methoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(p-methoxyphenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(3',4'-dichlorophenyl) 1-(2'-propenyloxycarbonyl) 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(para-fluorophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(p-chlorophenyl) 1-ethoxycarbonyl 2-aminomethyl cyclopropane (Z), the hydrochloride of 1-(p-hydroxyphenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), the hydrochloride of 1-(3',4',5'-trimethoxyphenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z), and the hydrochloride of 1-(ortho-bromophenyl) 1-ethoxycarbonyl 2-dimethylaminomethyl cyclopropane (Z). 